1508 Part IX / Diseases of the Nervous System
Figure 61–1 The hypothalamic-pituitary-adrenal axis.Neu-
rons in the paraventricular nucleus of the hypothalamus synthe-
size and release corticotropin-releasing hormone (CRH), the key
regulatory peptide in the hormonal cascade activated by stress.
The CRH neurons have a circadian pattern of secretion, and the
stimulatory effects of stress on CRH synthesis and secretion
are superimposed on this basal circadian pattern. Excitatory
fibers from the amygdala convey information about stressful
stimuli that activates CRH neurons; inhibitory fibers descend
from the hippocampus onto the paraventricular nucleus. CRH
enters the hypophyseal portal system and stimulates the
corticotropic cells in the anterior pituitary that synthesize and
release adrenocorticotropic hormone (ACTH). The released
ACTH enters the systemic circulation and stimulates the adre-
nal cortex to release glucocorticoids. In humans, the major
glucocorticoid is cortisol; in rodents, it is corticosterone. Both
cortisol and synthetic glucocorticoids such as dexamethasone
act at the level of the pituitary and hypothalamus to inhibit
further release of ACTH and CRH, respectively. The feedback
inhibition by glucocorticoids is attenuated in major depression
and the depressed phase of bipolar disorder. (Adapted, with
permission, from Nestler et al. 2015.)
effects of depression, such as increased release of stress
hormones (see below) and decreased motivation to
engage in rehabilitative regimens.
Depression and Stress Share Overlapping
Neural Mechanisms
Depression and responses to stress exhibit complex
but significant interactions. As already noted, severe
childhood adversity is a developmental risk factor for
depression; moreover, depressive episodes may be ini-
tiated by a stressful experience. Conversely, the expe-
rience of depression is itself stressful because of the
suffering it causes and its negative effects on function-
ing. Symptomatically, depression shares several physi-
ological features with chronic stress, including changes
in appetite, sleep, and energy. Both major depression
and chronic stress are associated with persistent acti-
vation of the HPA axis (Figure 61–1).
Many but not all individuals with major depres-
sion and many in the depressed phase of bipolar dis-
order exhibit excess synthesis and secretion of the
glucocorticoid stress hormone cortisol and the fac-
tors that regulate it, corticotropin-releasing hormone
(CRH) and adrenocorticotropic hormone (ACTH). In a
healthy state, a transient increase in cortisol secretion,
as occurs in response to acute stress, shifts the body to
a catabolic state (making glucose available to confront
the stressor or threat), increases subjective energy lev-
els, sharpens cognition, and may increase confidence.
However, a chronic increase in glucocorticoids may
contribute to depression-like symptoms. For example,
many people with Cushing disease (in which pituitary
tumors secrete excess ACTH, leading to excess cortisol)
experience symptoms of depression.
Feedback mechanisms within the HPA axis nor-
mally permit cortisol (or exogenously administered
glucocorticoids) to inhibit CRH and ACTH secretion
and therefore to suppress additional cortisol synthesis
and secretion. In approximately half of people with
major depression, this feedback system is impaired;
their HPA axis becomes resistant to suppression even
by potent synthetic glucocorticoids such as dexa-
methasone. Although readily measurable disturbances
of the HPA axis have not proven sensitive or specific
enough to be used as a diagnostic test for depression,
the observed abnormalities suggest strongly that a
pathologically activated stress response is often an
important component of depression.
The relationship of stress with depression has
led to the development of several chronic stress para-
digms in rodent models of depression. The reliance on
垂体
糖皮质激素类
促肾上腺
皮质激素
促肾上腺皮质激素释放激素
肾上腺
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–
–
大脑和
外周功能
的调节
海马体杏仁核
+
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